Bicyclic piperidine and piperazine derivatives as GPCR modulators for the treatment of obesity, diabetes and other metabolic disorders

Abstract

The present invention relates to Bicyclic Piperidine and piperazine Derivatives, compositions comprising a Bicyclic Piperidine and piperazine Derivative, and methods of using the Bicyclic Piperidine and piperazine Derivatives for treating or preventing obesity, diabetes, a metabolic disorder, a cardiovascular disease or a disorder related to the activity of a GPCR in a patient.

What is claimed is: 
     
       1. A compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
 A is aryl or -5- or 6-membered heteroaryl, wherein said aryl group or said -5- or 6-membered heteroaryl group can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-alkyl-OH, —O-alkyl-O-alkyl, —O-aryl, -alkylene-O-alkyl, —CN, —N(R 4 ) 2 , —C(O)H, —C(O)R 4 , —C(O)OR 4 , —C(O)N(R 4 ) 2 , —NHC(O)R 4 , —NHS(O) m R 4 , —S(O) n R 4  and —S(O) m N(R 4 ) 2 ; 
 B is aryl or heteroaryl, wherein said aryl group or said heteroaryl group can be the same or different, and are selected from alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, —OH, —O-haloalkyl, —O-alkyl, —O-aryl, -alkylene-O-alkyl, -alkylene-S(O) 2 -alkyl, —CN, —N(R 4 ) 2 , —C(O)R 4 , —C(O)OR 4 , —C(O)N(R 4 ) 2 , —NHC(O)R 4 , —NHS(O) m R 4 , —S(O) n R 4  and —S(O) m N(R 4 ) 2 , wherein said cycloalkyl or said heteroaryl substituent group can be unsubstituted or optionally substituted with R 9 , and wherein when B is aryl, the aryl group can be optionally fused to a 4 to 7-membered cycloalkyl group or cycloalkanoyl group; 
 W is —C(O)O—, alkylene, —C(O)—, —C(O)—O—, —S(O) 2 —, —S(O) 2 —N(R 7 )— or —C(O)—N(R 7 )—; 
 X is —C(R 1 ) 2 —, —O—, —N(R 10 )— or —S—; 
 Y is a bond, alkylene, -(alkylene) t -O-(alkylene) t -, -(alkylene) t -N(R 12 )-(alkylene) t - or -(alkylene) t -S-(alkylene) t -; 
 Z is C(R 7 ); 
 each occurrence of R 1  is independently H, alkyl, cycloalkyl, halo or —OR 7 ; wherein said alkyl group can be unsubstituted or optionally substituted with one or more of the following groups: —O-alkyl, —OH or —N(R 4 ) 2 ; and wherein any two geminal R 1  groups, together with the common carbon atom to which they are attached, can join to form a spirocyclic 3- to 6-membered cycloalkyl group, a spirocyclic 3- to 6-membered heterocycloalkyl group or a spirocyclic 3- to 6-membered heterocycloalkenyl group; and wherein any two R 1  groups present on separate ring carbon atoms can join to form a cycloalkyl or heterocycloalkyl bridge; and wherein any particular R 1  group is —OH, then any other R 1  group attached to the same carbon atom must be other than halo or —OR 7 ; 
 each occurrence of R 2a  is H or alkyl, wherein: (i) any two R 2a  groups, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; (ii) an R 2a  group and an R 2b  group, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; or (iii) R 7  and an R 2a  group that is attached to a carbon atom adjacent to Z, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; 
 each occurrence of R 2b  is H or alkyl, wherein (i): any two R 2b  groups, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; or (ii) an R 2b  group and an R 2a  group, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; 
 R 3  is alkyl, alkenyl, alkynyl, haloalkyl, -alkylene-O-(alkylene) t -aryl, -alkylene-S-aryl, -alkylene-N(R 4 )C(O)O-alkyl, —CH(cycloalkyl) 2 , —CH(heterocycloalkyl) 2 , -(alkylene) t -aryl, -(alkylene) t -cycloalkyl, -(alkylene) t -cycloalkenyl, -(alkylene) t -heterocycloalkyl, -(alkylene) t -heterocycloalkenyl or -(alkylene) t -heteroaryl, wherein said aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups can be unsubstituted or optionally substituted with R 8 ; 
 each occurrence of R 4  is H, alkyl, cycloalkyl or -(alkylene) t -alkenyl, wherein said alkyl group can be optionally substituted with halo, —OH or —O-alkyl; 
 each occurrence of R 4a  is H or alkyl, wherein (i) any two R 4a  groups, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group, (ii) an R 4a  group and an R 4b  group, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group, or (iii) R 7  and an R 4a  group that is attached to a carbon atom adjacent to Z, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; 
 each occurrence of R 4b  is H or alkyl, wherein (i) any two R 4b  groups, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group, or (ii) an R 4b  group and an R 4a  group, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; 
 R 7  is H or alkyl, or: (i) R 7  and an R 2a  group that is attached to a carbon atom adjacent to Z, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group, or (ii) R 7  and an R 4a  group that is attached to a carbon atom adjacent to Z, together with the carbon atoms to which each are attached, can join to form a cycloalkyl or heterocycloalkyl group; 
 R 8  is aryl, heteroaryl, heterocycloalkenyl, cycloalkenyl, cycloalkyl or heterocycloalkyl, any of which can be optionally substituted with R 9 ; 
 R 9  represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, —CN, —NO 2 , —O-(alkylene) t -R 13 , —S-(alkylene) t -R 13 , —N(R 13 )-(alkylene) t -R 13 , -(alkylene) t -R 13 , —C(O)-(alkylene) t -R 13 , —C(O)O-(alkylene) t -R 13 , —N(R 7 )C(O)-(alkylene) t -R 13 , —C(O)N(R 7 )-(alkylene) t -R 13 , —OC(O)-(alkylene) t -R 13 , —N(R 7 )C(O)N(R 7 )-(alkylene) t -R 13 , —N(R 7 )C(O)O-(alkylene) t -R 13 , —S(O)-(alkylene) t -R 13  or —S(O) 2 (alkylene) t -R 13 ; 
 R 10  is H, alkyl, aryl, or —C(O)OR 4 , wherein said alkyl group is unsubstituted or optionally substituted with —OH or —O-alkyl; 
 R 12  is H, alkyl or aryl; 
 each occurrence of R 13  is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl; 
 each occurrence of m is independently 1 or 2; 
 each occurrence of n is independently 0, 1 or 2, such that the sum of n and m is an integer ranging from 0 to 4; 
 p is an integer ranging from 0 to 4; 
 q is an integer ranging from 0 to 4; and 
 each occurrence of t is independently 0 or 1, 
 such that (i) at least one of R 2a , R 2b , R 4a  or R 4b , and the carbon atom to which it is attached, must combine with a separate R 2a , R 2b , R 4a  or R 4b  group and the carbon atom to which it is attached, to form a cycloalkyl or heterocycloalkyl group, or (ii) R 7  and an R 2a  group that is attached to a carbon atom adjacent to Z, together with the carbon atoms to which each are attached, must combine to form a cycloalkyl or heterocycloalkyl group, or (iii) R 7  and an R 4a  group that is attached to a carbon atom adjacent to Z, together with the carbon atoms to which each are attached, must combine to form a cycloalkyl or heterocycloalkyl group. 
 
     
     
       2. The compound of  claim 1 , wherein A and B are each independently aryl or 5- or 6-membered heteroaryl. 
     
     
       3. The compound of  claim 1 , wherein Y is —O— or —NH—, and the group B—X-A- is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein Q is H, halo, alkyl or —O-alkyl. 
     
     
       4. The compound of  claim 1 , wherein the group B—X-A- is: 
       
         
           
           
               
               
           
         
       
     
     
       5. The compound of  claim 1 , wherein the group B—X-A-Y— is: 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1 , wherein the group: 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 3 , wherein the group: 
       
         
           
           
               
               
           
         
       
     
     
       8. A compound having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
       9. A composition comprising an effective amount of one or more compounds of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier. 
     
     
       10. The composition of  claim 9 , further comprising an effective amount of one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from antidiabetic agents and antiobesity agents. 
     
     
       11. The composition of  claim 10 , wherein the antidiabetic agents are selected from an insulin sensitizer, an α-glucosidase inhibitor, a DPP-IV inhibitor, an insulin secretagogue, an hepatic glucose output lowering compound, an antihypertensive agent, a sodium glucose uptake transporter 2 (SGLT-2) inhibitor, insulin and an insulin-containing composition. 
     
     
       12. The composition of  claim 10 , wherein the antiobesity agents are selected from a neuropeptide Y antagonist, an MCR4 agonist, an MCH receptor antagonist, a protein hormone, an AMP kinase activator, a CB1 antagonist, a GLP-1 agonist and a lipase inhibitor. 
     
     
       13. A method for treating diabetes, obesity or metabolic syndrome in a patient, the method comprising administering to the patient an effective amount of one or more compounds of  claim 1  or a pharmaceutically acceptable salt or stereoisomer thereof. 
     
     
       14. The method of  claim 13 , wherein the treating is for diabetes. 
     
     
       15. The method of  claim 14 , wherein the treating is for type II diabetes. 
     
     
       16. The method of  claim 13 , wherein the treating is for obesity. 
     
     
       17. The method of  claim 13 , further comprising administering an effective amount of one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from antidiabetic agents and antiobesity agents.